Pyrimidine compounds

ABSTRACT

Compounds of the formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and p are as defined within and a pharmaceutically acceptable salts and (in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.

The invention relates to pyrimidine derivatives, or pharmaceuticallyacceptable salts or in vivo hydrolysable esters thereof, which possesscell-cycle inhibitory activity and are accordingly useful for theiranti-cell-proliferation (such as anti-cancer) activity and are thereforeuseful in methods of treatment of the human or animal body. Theinvention also relates to processes for the manufacture of saidpyrimidine derivatives, to pharmaceutical compositions containing themand to their use in the manufacture of medicaments of use in theproduction of an anti-cell-proliferation effect in a warm-blooded animalsuch as man.

A family of intracellular proteins called cyclins play a central role inthe cell cycle. The synthesis and degradation of cyclins is tightlycontrolled such that their level of expression fluctuates during thecell cycle. Cyclins bind to cyclin-dependent serine/threonine kinases(CDKs) and this association is essential for CDK (such as CDK1, CDK2,CDK4 and/or CDK6) activity within the cell. Although the precise detailsof how each of these factors combine to regulate CDK activity is poorlyunderstood, the balance between the two dictates whether or not the cellwill progress through the cell cycle.

The recent convergence of oncogene and tumour suppressor gene researchhas identified regulation of entry into the cell cycle as a key controlpoint of mitogenesis in tumours. Moreover, CDKs appear to be downstreamof a number of oncogene signalling pathways. Disregulation of CDKactivity by upregulation of cyclins and/or deletion of endogenousinhibitors appears to be an important axis between mitogenic signallingpathways and proliferation of tumour cells.

Accordingly it has been recognised that an inhibitor of cell cyclekinases, particularly inhibitors of CDK2, CDK4 and/or CDK6 (whichoperate at the S-phase, G1-S and G1-S phase respectively) should be ofvalue as a selective inhibitor of cell proliferation, such as growth ofmammalian cancer cells.

The present invention is based on the discovery that certain pyrimidinecompounds surprisingly inhibit the effects of cell cycle kinases showingselectivity for CDK2, CDK4 and CDK6, and thus possessanti-cell-proliferation properties. Such properties are expected to beof value in the treatment of disease states associated with aberrantcell cycles and cell proliferation such as cancers (solid tumours andleukemias), fibroproliferative and differentiative disorders, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation.

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkyyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl;wherein R² may be optionally substituted on carbon by one or moremethyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; andwherein if said heterocyclyl contains an —NH— moiety that nitrogen maybe optionally substituted by one or more methyl, ethyl, acetyl,2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

-   -   R⁵ is C₁₋₆alkyl or C₂₋₆alkenyl; wherein R⁵ may be optionally        substituted on carbon by one or more methoxy, ethoxy, propoxy,        trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or        cyclopropylmethoxy;

R⁶ is halo or C₁₋₄alkyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; with the proviso that if R⁴, R⁵ and R⁶ are all methyl then R²isnot hydrogen, optionally substituted C₁₋₄alkyl or C₃₋₆cycloalkyl.

In a further aspect of the invention there is provided a compound offormula (I) (as depicted above) wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl;wherein R² may be optionally substituted on carbon by one or moremethyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; andwherein if said heterocyclyl contains an —NH— moiety that nitrogen maybe optionally substituted by one or more methyl, ethyl, acetyl,2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₂₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is C₁₋₆alkyl or C₂₋₆alkenyl; wherein R⁵ may be optionally substitutedon carbon by one or more methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy;

R⁶ is C₁₋₄alkyl; or a pharmaceutically acceptable salt or an in vivohydrolysable ester thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl”, “C₂₋₆alkyl”, “C₁₋₄alkyl”, “C₂₋₄alkyl” and“C₁₋₃alkyl” include propyl, isopropyl and t-butyl. However, referencesto individual alkyl groups such as ‘propyl’ are specific for thestraight chained version only and references to individual branchedchain alkyl groups such as ‘isopropyl’ are specific for the branchedchain version only. A similar convention applies to other radicals, forexample “C₃₋₆cycloalkylC₁₋₃alkyl” includes cyclopropylmethyl,1-cyclobutylethyl and 3-cyclopropylpropyl. The term “halo” refers tofluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,monocyclic ring containing 4-6 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, and a ring sulphur atom may beoptionally oxidised to form the S-oxide(s). Examples and suitable valuesof the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl,pyrrolyl, isothiazolyl, thienyl, thiadiazolyl, piperazinyl,thiazolidinyl, thiomorpholino, pyrrolinyl, tetrahydropyranyl,tetrahydrofuryl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl andisoxazolyl. Suitably a “heterocyclyl” is tetrahydrofuryl.

Examples of “C₁₋₃alkoxy” include, methoxy, ethoxy and propoxy. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₄alkynyl” are ethynyl, 1-propynyl and 2-propynyl.Examples of “C₃₋₆cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Examples of “heterocyclylC₁₋₃alkyl” includepyridylmethyl, 3-morpholinopropyl and 2-pyrimid-2-ylethyl. Examples of“C₁₋₆alkoxyC₁₋₆alkyl” and “C₁₋₄alkoxyC₁₋₄alkyl” are methoxymethyl,2-methoxyethyl and 2-ethoxypropyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobroric, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4 position of the benzoyl ring.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess CDK inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess CDK inhibitory activity. In particularthe skilled reader will appreciate that when R⁴ is hydrogen, theimidazole ring as drawn in formula (I) may tautomerise.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess CDK inhibitory activity.

Suitable values of R¹, R², R³, R⁴, R⁵, R⁶ and p are as follows. Suchvalues may be used where appropriate with any of the definitions, claimsor embodiments defined hereinbefore or wherein:

R¹ is fluoro, chloro, cyano, methyl, ethyl, methoxy or ethoxy.

p is 0.

p is 1.

p is 2; wherein the values of R¹ may be the same or different.

R² is hydrogen or C₁₋₄alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy or ethoxy.

R² is hydrogen, C₁₋₄alkyl or heterocyclylC₁₋₃alkyl; wherein R² may beoptionally substituted on carbon by one or more methoxy or ethoxy.

R² is hydrogen, methyl, ethyl or propyl; wherein R² may be optionallysubstituted on carbon by one or more methoxy or ethoxy.

R² is hydrogen, methyl, ethyl, propyl or 2-pyrazolylethyl; wherein R²may be optionally substituted on carbon by one or more methoxy orethoxy.

R² is hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or2-ethoxyethyl.

R² is hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or 2-ethoxyethylor 2-pyrazol-1-ylethyl.

R³ is hydrogen.

R³ is hydrogen or halo.

R³ is hydrogen or bromo.

R⁴ is C₂₋₄alkyl.

R⁴ is C₁₋₄alkyl.

R⁴ is ethyl or isopropyl.

R⁴ is methyl, ethyl or isopropyl.

R⁵ is C₁₋₆alkyl.

R⁵ is C₁₋₄alkyl.

R⁵ is methyl or ethyl.

R⁶ is methyl.

R⁶ is methyl or halo.

R⁶ is methyl or bromo.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen or C₁₋₄alkyl; wherein R² may be optionally substituted oncarbon by one or more methoxy or ethoxy;

R³ is hydrogen;

R⁴ is C₂₋₄alkyl;

R⁵ is C₁₋₆alkyl;

R⁶ is methyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.

Therefore in another aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, C₁₋₄alkyl or heterocyclylC₁₋₃alkyl; wherein R² may beoptionally substituted on carbon by one or more methoxy or ethoxy;

R³ is hydrogen or halo;

R⁴ is C₁₋₄alkyl;

R⁵ is C₁₋₆alkyl;

R⁶ is methyl or halo;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; with the proviso that if R⁴, R⁵ and R⁶are all methyl then R² isnot hydrogen or optionally substituted C₁₋₄alkyl.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or2-ethoxyethyl;

R³ is hydrogen;

R⁴ is ethyl or isopropyl;

R⁵ is methyl or ethyl;

R⁶ is methyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or 2-ethoxyethylor 2-pyrazol-1-ylethyl;

R³ is hydrogen or bromo;

R⁴ is methyl, ethyl or isopropyl;

R⁵ is methyl or ethyl;

R⁶ is methyl or bromo;

or a pharmaceutically acceptable salt or an in vivo hydrolysable esterthereof; with the proviso that if R⁴, R⁵ and R⁶ are all methyl then R²is not hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or2-ethoxyethyl.

In another aspect of the invention, particular compounds of theinvention are any one of the Examples or a pharmaceutically acceptablesalt or an in vivo hydrolysable ester thereof.

A particular aspect of the invention is that which relates to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt or an invivo hydrolysable ester thereof which process (wherein R¹, R², R³, R⁴,R⁵, R⁶ and p are, unless otherwise specified, as defined in formula (I))comprises of:

-   Process a) Reaction of a Pyrimidine of Formula (II):    wherein L is a displaceable group; with an aniline of formula (III):-   Process b) Reacting a Compound of Formula (IV):    with a compound of formula (V):    wherein T is O or S; R^(x) may be the same or different and is    C₁₋₆alkyl;-   Process c) Reacting a Pyrimidine of Formula (VI):    wherein X is a displaceable group; with an amine of formula (VII):    R²—NH₂  (VII)    or-   Process d) Reacting a Pyrimidine of Formula (VIII)    with a compound of formula (IX):    where Y is a displaceable group;    and thereafter if necessary:-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt or in vivo    hydrolysable ester.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

X is a displaceable group, suitable values for X are for example, afluoro or chloro group. Preferably X is fluoro.

Y is a displaceable group, suitable values for Y are for example, ahalogeno or sulphonyloxy group, for example a bromo, iodo ortrifluoromethanesulphonyloxy group. Preferably Y is iodo.

Specific reaction conditions for the above reactions are as follows.

-   Process a) Pyrimidines of Formula (II) and Anilines of Formula (II)    may be Reacted Together:-   i) in the presence of a suitable solvent for example a ketone such    as acetone or an alcohol such as ethanol or butanol or an aromatic    hydrocarbon such as toluene or N-methyl pyrrolidine, optionally in    the presence of a suitable acid for example an inorganic acid such    as hydrochloric acid or sulphuric acid, or an organic acid such as    acetic acid or formic acid (or a suitable Lewis acid) and at a    temperature in the range of 0° C. to reflux, preferably reflux; or-   ii) under standard Buchwald conditions (for example see J. Am. Chem.    Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62,    1568 and 6066) for example in the presence of palladium acetate, in    a suitable solvent for example an aromatic solvent such as toluene,    benzene or xylene, with a suitable base for example an inorganic    base such as caesium carbonate or an organic base such as    potassium-t-butoxide, in the presence of a suitable ligand such as    2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and at a temperature in    the range of 25 to 80° C.

Pyrimidines of the formula (II) where L is chloro may be preparedaccording to Scheme 1:

Anilines of formula (III) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process b) Compounds of formula (IV) and compounds of formula (V)    are reacted together in a suitable solvent such as    N-methylpyrrolidinone or butanol at a temperature in the range of    100-200° C., preferably in the range of 150-170° C. The reaction is    preferably conducted in the presence of a suitable base such as, for    example, sodium hydride, sodium methoxide or potassium carbonate.

Compounds of formula (V) may be prepared according to Scheme 2:

Compounds of formula (IV) and (Va) are commercially available compounds,or they are known in the literature, or they are prepared by standardprocesses known in the art.

-   Process c) Compounds of formula (VI) and amines of formula (VII) may    be reacted together in the presence of an inert solvent such as    N-methylpyrrolidinone or pyridine, in the presence of a base for    example an inorganic base such as caesium carbonate or in the    presence of an organic base such as excess (VII) and at a    temperature in the range of 25 to 80° C.

Compounds of formula (VI) (wherein X is chloro) may be preparedaccording to Scheme 3:

Compounds of formula (VIa) may be prepared according to Process a,Process b or Process d but wherein compounds (III), (IV) and (IX) arenot substituted by R²NHSO₂—.

-   Process d) Compounds of formula (VIII) and amines of formula (IX)    may be reacted together under standard Buchwald conditions as    described in Process a.

The synthesis of compounds of formula (VIM) is described in Scheme 1.

Compounds of formula (IX) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Amines of formula (VI) are commercially available compounds, or they areknown in the literature, or they are prepared by standard processesknown in the art.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment to with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossesses anti-cell-proliferation activity such as anti-cancer activitywhich is believed to arise from the CDK inhibitory activity of thecompound. These properties may be assessed, for example, using theprocedures set out in WO 02/04429.

Although the pharmacological properties of the compounds of the formula(I) vary with structural change, in general activity possessed bycompounds of the formula (I) may be demonstrated at IC₅₀ concentrationsor doses in the range 250 μM to 1 nM in the in vitro assay described inWO 02/04429.

Typical IC₅₀ values for compounds of the invention when tested in theSRB assay described in WO 02/04429 are in the range 1 mM to 1 nM.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a pyrimidine derivative ofthe formula (I), or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof, as defined hereinbefore in association witha pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-50mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt orin vivo hydrolysable ester thereof, as defined hereinbefore for use in amethod of treatment of the human or animal body by therapy.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,are effective cell cycle inhibitors (anti-cell proliferation agents),which property is believed to arise from their CDK inhibitoryproperties. Accordingly the compounds of the present invention areexpected to be useful in the treatment of diseases or medical conditionsmediated alone or in part by CDK enzymes, i.e. the compounds may be usedto produce a CDK inhibitory effect in a warm-blooded animal in need ofsuch treatment. Thus the compounds of the present invention provide amethod for treating the proliferation of malignant cells characterisedby inhibition of CDK enzymes, i.e. the compounds may be used to producean anti-proliferative effect mediated alone or in part by the inhibitionof CDKs. Such a compound of the invention is expected to possess a widerange of anti-cancer properties as CDKs have been implicated in manycommon human cancers such as leukaemia and breast, lung, colon, rectal,stomach, prostate, bladder, pancreas and ovarian cancer. Thus it isexpected that a compound of the invention will possess anti-canceractivity against these cancers. It is in addition expected that acompound of the present invention will possess activity against a rangeof leukaemias, lymphoid malignancies and solid tumours such ascarcinomas and sarcomas in tissues such as the liver, kidney, prostateand pancreas. In particular such compounds of the invention are expectedto slow advantageously the growth of primary and recurrent solid tumoursof, for example, the colon, breast, prostate, lungs and skin. Moreparticularly such compounds of the invention, or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof, are expected toinhibit the growth of those primary and recurrent solid tumours whichare associated with CDKs, especially those tumours which aresignificantly dependent on CDKs for their growth and spread, includingfor example, certain tumours of the colon, breast, prostate, lung, vulvaand skin. Particularly “cancer” is selected from leukaemia, breastcancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer,bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidneycancer, skin cancer and cancer of the vulva.

It is further expected that a compound of the present invention willpossess activity against other cell-proliferation diseases in a widerange of other disease states including leukaemias, fibroproliferativeand differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined hereinbefore for use as amedicament; and the use of a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined hereinbefore in the manufacture of a medicament for use inthe production of a cell cycle inhibitory (anti-cell-proliferation)effect in a warm-blooded animal such as man. Particularly, an inhibitoryeffect is produced by preventing entry into or progression through the Sphase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.

According to a further feature of the invention, there is provided acompound of the formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof, as defined herein before in themanufacture of a medicament for use in the treatment of cancers (solidtumours and leukaemias), fibroproliferative and differentiativedisorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,arterial restenosis, autoimmune diseases, acute and chronicinflammation, bone diseases and ocular diseases with retinal vesselproliferation, particularly in the treatment of cancers.

According to a further feature of this aspect of the invention there isprovided a method for producing a cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound as defined immediately above.Particularly, an inhibitory effect is produced by preventing entry intoor progression through the S phase by inhibition of CDK2, CDK4 and/orCDK6, especially CDK2.

According to a further feature of this aspect of the invention there isprovided a method for producing a cell cycle inhibitory(anti-cell-proliferation) effect in a warm-blooded animal, such as man,in need of such treatment which comprises administering to said animalan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof as defined hereinbefore. Particularly, an inhibitory effect is produced by preventingentry into or progression through the S phase by inhibition of CDK2,CDK4 and/or CDK6, especially CDK2.

According to an additional feature of this aspect of the invention thereis provided a method of treating cancers (solid tumours and leukaemias),fibroproliferative and differentiative disorders, psoriasis, rheumatoidarthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,autoimmune diseases, acute and chronic inflammation, bone diseases andocular diseases with retinal vessel proliferation, in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof as defined herein before.

Particularly there is provided a method of treating cancer in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof as defined herein before.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or ill vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the productionof a cell cycle inhibitory (anti-cell-proliferation) effect in awarm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the treatmentof cancers (solid tumours and leukaemiias), fibroproliferative anddifferentiative disorders, psoriasis, rheumatoid arthritis, Kaposi'ssarcoma, haemangioma, acute and chronic nephropathies, atheroma,atherosclerosis, arterial restenosis, autoimmune diseases, acute andchronic inflammation, bone diseases and ocular diseases with retinalvessel proliferation, in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the treatmentof cancer in a warm-blooded animal such as man.

Preventing cells from entering DNA synthesis by inhibition of essentialS-phase initiating activities such as CDK2 initiation may also be usefulin protecting normal cells of the body from toxicity of cycle-specificpharmaceutical agents. Inhibition of CDK2 or 4 will prevent progressioninto the cell cycle in normal cells which could limit the toxicity ofcycle-specific pharmaceutical agents which act in S-phase, G2 ormitosis. Such protection may result in the prevention of hair lossnormally associated with these agents.

Therefore in a further aspect of the invention there is provided acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof for use as a cellprotective agent.

Therefore in a further aspect of the invention there is provided acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof for use inpreventing hair loss arising from the treatment of malignant conditionswith pharmaceutical agents.

Examples of pharmaceutical agents for treating malignant conditions thatare known to cause hair loss include alkylating agents such asifosfamide and cyclophosphamide; antimetabolites such as methotrexate,5-fluorouracil, gemcitabine and cytarabine; vinca alkaloids andanalogues such as vincristine, vinbalstine, vindesine, vinorelbine;taxanes such as paclitaxel and docetaxel; topoisomerase I inhibitorssuch as irintotecan and topotecan; cytotoxic antibiotics such asdoxorubicin, daunorubicin, mitoxantrone, actinomycin-D and mitomycin;and others such as etoposide and tretinoin.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt or in vivo hydrolysable ester thereof,may be administered in association with a one or more of the abovepharmaceutical agents. In this instance the compound of formula (I) maybe administered by systemic or non systemic means. Particularly thecompound of formula (I) my may administered by non-systemic means, forexample topical administration.

Therefore in an additional feature of the invention, there is provided amethod of preventing hair loss during treatment for one or moremalignant conditions with pharmaceutical agents, in a warm-bloodedanimal, such as man, which comprises administering to said animal aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof.

In an additional feature of the invention, there is provided a method ofpreventing hair loss during treatment for one or more malignantconditions with pharmaceutical agents, in a warm-blooded animal, such asman, which comprises administering to said animal an effective amount ofa compound of formula (I), or a pharmaceutically acceptable salt or invivo hydrolysable ester thereof in simultaneous, sequential or separateadministration with an effective amount of said pharmaceutical agent.

According to a further aspect of the invention there is provided apharmaceutical composition for use in preventing hair loss arising fromthe treatment of malignant conditions with pharmaceutical agents whichcomprises a compound of formula (I), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof, and said pharmaceuticalagent, in association with a pharmaceutically acceptable diluent orcarrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester thereof, and apharmaceutical agent for treating malignant conditions that is known tocause hair loss.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt    or in vivo hydrolysable ester thereof, in a first unit dosage form;-   b) a pharmaceutical agent for treating malignant conditions that is    known to cause hair loss; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltor in vivo hydrolysable ester thereof, in the manufacture of amedicament for the prevention of hair loss during treatment of malignantconditions with pharmaceutical agents.

According to a further aspect of the present invention there is provideda combination treatment for the prevention of hair loss comprising theadministration of an effective amount of a compound of the formula (I),or a pharmaceutically acceptable salt or in vivo hydrolysable esterthereof, optionally together with a pharmaceutically acceptable diluentor carrier, with the simultaneous, sequential or separate administrationof an effective amount of a pharmaceutical agent for treatment ofmalignant conditions to a warm-blooded animal, such as man.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

The CDK inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. In thefield of medical oncology it is normal practice to use a combination ofdifferent forms of treatment to treat each patient with cancer. Inmedical oncology the other component(s) of such conjoint treatment inaddition to the cell cycle inhibitory treatment defined hereinbefore maybe: surgery, radiotherapy or chemotherapy. Such chemotherapy may coverthree main categories of therapeutic agent:

-   (i) other cell cycle inhibitory agents that work by the same or    different mechanisms from those defined hereinbefore;-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen,torernifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LIRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors); and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites.(for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincristine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan). According to this aspect of the invention there is    provided a pharmaceutical product comprising a compound of the    formula (I) as defined hereinbefore and an additional anti-tumour    substance as defined hereinbefore for the conjoint treatment of    cancer.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of cell cycle activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutic agents.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated by the following non limitingexamples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations    were carried out at room or ambient temperature, that is, at a    temperature in the range of 18-25° C.;-   (ii) organic solutions were dried over anhydrous magnesium sulphate;    evaporation of solvent was carried out using a rotary evaporator    under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath    temperature of up to 60° C.;-   (iii) chromatography means flash chromatography on silica gel; thin    layer chromatography (TLC) was carried out on silica gel plates;-   (iv) in general, the course of reactions was followed by TLC and    reaction times are given for illustration only;-   (v) final products had satisfactory proton nuclear magnetic    resonance (NMR) spectra and/or mass spectral data;-   (vi) yields are given for illustration only and are not necessarily    those which can be obtained by diligent process development;    preparations were repeated if more material was required;-   (vii) when given, NMR data is in the form of delta values for major    diagnostic protons, given in parts per million (ppm) relative to    tetramethylsilane dIMS) as an internal standard, determined at 300    MHz using perdeuterio dimethyl sulphoxide (DMSO-d₆) as solvent    unless otherwise indicated;-   (viii) chemical symbols have their usual meanings; SI units and    symbols are used;-   (ix) solvent ratios are given in volume:volume (v/v) terms; and-   (x) mass spectra were run with an electron energy of 70 electron    volts in the chemical ionization (CI) mode using a direct exposure    probe; where indicated ionization was effected by electron impact    (EI), fast atom bombardment (FAB) or electrospray (ESP); values for    m/z are given; generally, only ions which indicate the parent mass    are reported; and unless otherwise stated, the mass ion quoted is    (MH)⁺;-   (xi) unless stated otherwise compounds containing an asymmetrically    substituted carbon and/or sulphur atom have not been resolved;-   (xii) where a synthesis is described as being analogous to that    described in a previous example the amounts used are the millimolar    ratio equivalents to those used in the previous example;

(xvi) the following abbreviations have been used: DMF.DMAdimethylformamide dimethylacetal; DMA dimethylacetal; EtOAc ethylacetate; MeOH methanol; and DCM dichloromethane;

-   xvii) where an Isolute SCX-2 column is referred to, this means an    “ion exchange” extraction cartridge for adsorption of basic    compounds, i.e. a polypropylene tube containing a benzenesulphonic    acid based strong cation exchange sorbent, used according to the    manufacturers instructions obtained from International Sorbent    Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,    UK, CF82 7RJ;-   xviii) where an Isolute amine column is referred to, this means an    “ion exchange” extraction cartridge for adsorption of acidic    compounds, i.e. a polypropylene tube containing a amino silane    covalently bonded to a silica particle used according to the    manufacturers instructions obtained from International Sorbent    Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,    UK, CF82 7RJ; and-   xix) where a Chemelut column is referred to, this means an    extraction cartridge for removal of water, i.e. a polypropylene tube    containing diatomaceous earth used according to the manufacturers    instructions obtained from Varian, Harbor City, Calif., U.S.A.

Example 14-(1.2-Diethyl-4-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solutionof 2-anilino-4-(1,2-diethylmethylimidazol-5-yl)pyrimidine (Method 13; 28mg, 0.09 mmol) in thionyl chloride (2 ml) cooled at 0° C. and themixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90minutes. The volatiles were removed by evaporation and the residue wasdried under high vacuum (<2 mmHg) for 1 hour. The resulting solid wasplaced under nitrogen and a solution of 2-methoxyethylamine (300 μl,3.45 mmol) in isopropanol (2 ml) added. The mixture was stirred for 30minutes and the volatiles were evaporated in vacuo. Water (20 ml) wasadded and extracted EtOAc (2×20ml). The organic layers were combined,dried and evaporated in vacuo to give the title compound (16 mg, 40%) asa orange solid. NMR 2.35-2.45 (m, 9H), 2.7 (q, 2H), 2.89 (q, 2H),3.40-3.28 (m, 2H), 3.60-3.58 (m, 3H), 4.35 (m, 2H), 7.0 (d, 1H), 7.49(t, 1H), 7.70 (d, 2H), 7.9 (d, 2H), 8.55 (d, 1H); m/z 445.

Examples 2-10

The following compounds were prepared by the procedure of Example 1using the appropriate starting materials.

Ex R¹ R² NMR M/z SM  2 Et EtO—(CH₂)₂— 1.05(m, 6H), 2.24(s, 3H), 2.35(s,3H), 445 Meth 11 2.87(q, 2H), 3.34(m, 4H), 4.30(q, 2H), 6.92(d, 1H),7.42(t, 1H), 7.70(d, 2H), 7.90(d, 2H), 8.52(d, 1H), 9.90(s, 1H)  3 EtMeO—(CH₂)₂— 1.16(t, 3H), 1.59(q, 2H), 2.25(s, 3H), 445 Meth 11 2.38(s,3H), 2.75(q, 2H), 3.17(s, 3H), 3.26(m, 2H), 4.35(q, 2H), 6.97(d, 1H),7.34(t, 1H), 7.69(d, 2H), 7.94(d, 2H), 8.53(d, 1H), 9.90(s, 1H)  4 EtMeO—(CH₂)₂— 1.06(t, 3H), 2.24(s, 3H), 2.35(s, 3H), 431 Meth 11 2.87(q,2H), 3.16(s, 3H), 3.28(m, 2H), 4.35(q, 2H), 6.98(d, 1H), 7.45(t, 1H),7.70(d, 2H), 7.90(d, 2H), 8.55(d, 1H), 9.89(s, 1H)  5 Et Me 1.10(t, 3H),2.24(s, 3H), 2.36(s, 3H), 387 Meth 11 2.39(d, 3H), 4.37(q, 2H), 6.98(d,1H), 7.18(q, 1H), 7.66(d, 2H), 7.92(d, 2H), 8.50(d, 1H), 9.89(s, 1H)  6¹Et H 1.08(t, 3H), 2.25(s, 3H), 2.36(s, 3H), 373 Meth 11 4.35(q, 2H),6.95(d, 1H), 7.16(s, 2H), 7.71(d, 2H), 7.89(d, 2H), 8.53(d, 1H), 9.85(s,1H)  7 i-Pr MeO—(CH₂)₂— 1.4(d, 6H), 2.15(s, 3H), 2.42(s, 3H), 2.86 445Meth 12 (q, 2H), 3.17(s, 3H), 3.27(m, 2H), 4.93(q, 1H), 6.90(d, 1H),7.48(t, 2H), 7.70(d, 2H), 7.93(d, 2H), 8.55(d, 1H), 9.90(s, 1H)  8 i-PrMeO—(CH₂)₃— 1.40(d, 6H), 1.55(q, 2H), 2.15(s, 3H), 459 Meth 12 2.42(s,3H), 2.75(q, 2H), 3.15(s, 3H), 3.28(m, 2H), 4.94(q, 1H), 6.90(d, 1H),7.36(t, 1H), 7.65(d, 2H), 7.92(d, 2H), 8.55(d, 1H), 9.90(s, 1H)  9¹ i-PrH 1.45(d, 6H), 2.15(s, 3H), 2.45(s, 3H), 387 Meth 12 4.95(q, 1H),6.92(d, 1H), 7.16(s, 2H), 7.70(d, 2H), 7.90(d, 2H), 8.55(d, 1H), 9.95(s,1H) 10 i-Pr EtO—(CH₂)₂— 1.05(t, 3H), 1.40(d, 6H), 2.18(s, 3H), 459 Meth12 2.39(s, 3H), 2.85(q, 2H), 3.32(m, 2H), 4.94(q, 1H), 6.92(d, 1H),7.45(t, 1H), 7.69(d, 2H), 7.93(d, 2H), 8.55(d, 1H), 9.90(s, 1H) 11 i-PrMe 1.40(d, 6H), 2.15(s, 3H), 2.39(d, 3H), 400 Meth 12 2.45(s, 3H),4.95(q, 1H), 6.92(d, 1H), 7.20(q, 1H), 7.65(d, 2H), 7.94(d, 2H), 8.58(d,1H), 9.95(s, 1H) 12² Me (pyrazol-1- 2.30(s, 3H), 2.39(s, 3H), 3.09(q,2H), 453 Ex 31 in yl)(CH₂)₂— 3.78(s, 3H), 4.12(t, 2H), 6.19(s, 1H), 7.0WO (d, 1H), 7.39(s, 1H), 7.59(t, 1H), 7.63 02/20512 (d, 1H), 7.68(d,2H), 7.95(d, 2H), 8.57(d, 1H)¹Purified by flash silica chromatography DCM:MeOH (95:5)²9 equivalents of N,N-dimethylethylamine were added with2-(pyrazol-1yl)ethylamine hydrobromide (Method 14) and the final productwas purified by flash silica chromatography DCM:MeOH (96:4)

Example 134-(4Bromo-1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxvethyl)sulphamoyl]anilino}pyrimidine

A 1M solution of bromine in acetic acid (8.49 ml, 8.49 mmol) was addedto a solution of4(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine(Example 35 in WO 02/20512; 3.1g, 7.71mmol) in acetic acid (24 ml)heated at 70° C. under nitrogen. The mixture was stirred at 70° C. for 1hour, allowed to cool, diluted with water and carefully neutralised withsaturated aqueous sodium hydrogen carbonate solution. The aqueoussolution was extracted with EtOAc, the extracts combined, dried and thevolatiles removed by evaporation. The residue was purified bychromatography on silica gel eluting with DCM/MeOH (95:5 increasing inpolarity to 90:10) to give the title compound (1 g, 24%). NMR: 2.38 (s,3H), 2.87 (s, 2H), 2.51 (q, 2H), 3.16 (s, 3H), 3.52 (s, 3H), 7.49 (s,1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.82 (s, 1H).

Preparation of Starting Materials

The starting materials for the examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Methods 1-8

The following compounds were synthesised by the procedure as describedin JOC 1987, 2714-2716. Meth Compound NMR m/z SM 1 4-Amino-3,5- 2.03(s,3H), 2.19(s, 3H), ND 4-Nitro-3,5-dimethylisoxazole dimethylisoxazole3.75(brs, 2H) 2 3,5-Methyl-4-(N- 1.99(s, 3H), 2.05(s, 3H), 154 Meth 1acetamido)isoxazole 2.22(s, 3H), 9.28(s, 1H). 3 3,5-Methyl-4- 1.02(t,3H), 2.18(s, 3H), No Meth 2 (ethylamino)isoxazole 2.29(s, 3H),2.85(quin, m/s 2H), 3.70(s, 1H) 4 3,5-Methyl-4-(N-ethyl-N- 0.96(t, 3H),1.70(s, 3H), No Meth 3 acetamido)isoxazole 1.92(s, 3H), 2.34(s, 3H), m/s3.24-3.35(m, 2H) 5 5-Acetyl-1-ethyl-2,4- 1.15(t, 3H), 2.30(s, 3H), 167Meth 4 dimethylimidazole 2.4(d, 6H), 4.18(q, 2H) 6 3,5-Methyl-4- 1.0(d,6H), 2.08(s, 3H), 154 4-amino-3,5- (isopropylamino)isoxazole 2.24(s,3H), 2.95-3.04(m, methylisoxazole 1H), 3.44(d, 1H) 73,5-Methyl-4-(N-isopropyl- 0.98(t, 6H), 1.63(s, 3H), Meth 6N-acetamido)isoxazole 2.10(s, 3H), 2.32(s, 3H), 4.67(m, 1H) 85-Acetyl-1-isopropyl-2,4- 1.39(d, 6H), 2.38(m, 9H), 181 Meth 7dimethylimidazole 5.08(q, 1H)Method 95-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2,4-dimethylimidazole

5-Acetyl-1-isopropyl-2,4-dimethylimidazole (Method 8; 3g, 16.5 mmol) wasdissolved in a mixture DMF.DMA (100 ml) and the mixture heated underreflux, under an atmosphere of nitrogen, for 18 hours. The volatileswere evaporated in vacuo. The residue was purified by flash silicachromatography DCM:MeOH (increasing in polarity from 100:0 to 95:5) togive the title compound (510 mg, 13%) as an orange oil. NMR 1.38 (d,6H), 2.18 (s, 3H), 2.30 (s, 3H), 2.83 (s, 3H), 3.08 (s, 3H), 4.72 (q,1H), 5.21 (d, 1H), 7.46 (d, 1H); m/z 236

Method 10

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2,4-dimethylimidazole

The title compound was prepared from Method 5 by the procedure of Method9 and used without further purification.

Method 11

2-Anilino-4-(1-ethyl-2,4dimethylimidazol-5-yl)pyrimidine

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2,4-dimethylimidazole (Method10; 5.65 g, 25.6 mmol), phenylguanidine hydrogen carbonate (6.05, 30.7mmol) and sodium methoxide (3.47 g, 64.2 mmol) were suspended inanhydrous DMA (80 ml) and the mixture heated at 150° C. for 18 hours.The reaction mixture was allowed to cool to ambient temperature andpoured into water (50 ml). The solution was extracted EtOAc (2×50 ml).The combined extracts were washed with water (2×50 ml) and then brine(2×50 ml), dried and the volatiles removed by evaporation. The residuepurified by flash silica chromatography DCM:MeOH (increasing in polarityfrom 100:0 to 96:4) to give the title compound (5.2 g, 70%) as an orangeoil. NMR: 1.06 (t, 3H), 2.22 (s, 3H), 2.34 (s, 3H), 4.32 (q, 2H), 6.83(d, 1H), 6.97 (t, 1H), 7.28 (t, 2H), 7.70 (d, 2H), 8.43 (d, 2H), 9.40(s, 1H); m/z 294.

Method 12

The following compound was prepared by the procedure of Method 11. MethCompound NMR m/z SM 12 2-Anilino-4-(1-isopropyl-2,4- 1.39(d, 6H),2.15(s, 3H), 2.41(s, 308 Meth 9 dimethylimidazol-5- 3H), 4.90(q, 1H),6.80(d, 1H), yl)pyrimidine 6.95(t, 1H), 7.24(t, 2H), 7.90(d, 2H),8.48(d, 1H), 9.49(s, 1H)Method 132-Anilino-4(1,2-diethyl-4-methlimidazol-5-yl)pyrimidine

2-Anilino4-(l-ethyl-2,4dimethylimidazol-5-yl)pyrimidine (Method 11; 200mg, 0.68 mmol) was dissolved in anhydrous THF (10 ml) under an inertatmosphere. The stirring solution was cooled using dry-ice/acetone bathto −70° C. A 1.6 M solution of n-butyl lithium in hexane (900 μl, 1.44mmol) was added drop-wise keeping temperature <−60° C. until the darkred colour remained. At this point 1.6 M n-butyl lithium in hexane (450μl, 0.72 mmol) was added and the solution stirred at −70° C. for 10minutes. Iodomethane (99 μl, 1.50 mmol) was added, the temperature wasmaintained at −70° C. for an additional 10 minutes then allowed to riseto room temperature. The reaction was allowed to stir for 1 hr at roomtemperature when water (100 ml) was added. The aqueous layer extractedwith EtOAc (2×20 ml). Organics were combined, dried solvent evaporatedin vacuo. The residue was purified by flash silica chromatographyDCM:MeOH (increasing in polarity from 100:0 to 96:4) to yield the titlecompound (28 mg, 13%). M/z 322.

Method 14

2-(Pyrazol-1yl)ethylamine Hydrobromide

Pyrazole (10.88 g, 160 mmol), in dry acetonitrile (80 ml) was added tosolid sodium hydroxide (22.96 g, 574 mol) and the mixture was stirredfor 30 minutes at ambient temperature. Tetrabutylammonium hydrogensulphate (2.18 g, 6.41 mmol) and 2-chloroethylamine hydrochloride (19.78g, 172 mmol) were added and the mixture heated at reflux for 24 hours.The mixture was allowed to cool, the insolubles removed by filtrationand the filtrate evaporated. Excess 49% hydrobromic acid, followed byethanol (100 ml), was added to the residue and the mixture heated toreflux, then cooled in ice. The resulting solid was collected byfiltration washed with cold ethanol and dried to give the titlecompound. NMR: 3.21 (s, 2H), 4.39 (t, 2H), 6.28 (s, 1H), 7.50 (s, 1H),7.79 (s, 1H), 7.96 (s, 2H).

Example 14

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), or a pharmaceutically acceptablesalt or in vivo hydrolysable ester thereof (hereafter compound X), fortherapeutic or prophylactic use in humans:- (a): Tablet I mg/tabletCompound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maizestarch paste (5% w/v paste) 2.25 Magnesium stearate 3.0

(b): Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0

(c): Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0

(d): Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesiumstearate 1.5

(e): Injection I (50 mg/ml) Compound X 5.0% w/v   1M Sodium hydroxidesolution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100%

(f): Injection II 10 mg/ml Compound X 1.0% w/v Sodium phosphate BP 3.6%w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100%

(g): Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

1. A compound of formula (I):

wherein: R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy; p is 0-2; wherein the values of R¹ may be the same or different; R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by one or more methyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl; R³ is hydrogen, halo or cyano; R⁴ is C₁₋₆alkyl or C₁₋₆akoxyC₁₋₆alkyl; R⁵ is C₁₋₆alkyl or C₂₋₄alkenyl; wherein R⁵ may be optionally substituted on carbon by one or more methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; R⁶ is halo or C₁₋₄alkyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; with the proviso that if R⁴, R⁵ and R⁶ are all methyl then R² is not hydrogen, optionally substituted C₁₋₄alkyl or C₃₋₆cycloalkyl:
 2. A compound of formula (I) according to claim 1 wherein p is 0; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 3. A compound of formula (I) according to claim 1 or 2 wherein R² is hydrogen, C₁₋₄alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methoxy or ethoxy; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 4. A compound of formula (I) according to anyone of claims 1-3 wherein R³ is hydrogen or halo; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 5. A compound of formula (I) according to anyone of claims 1-4 wherein R⁴ is C₁₋₄alkyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 6. A compound of formula (I) according to anyone of claims 1-5 wherein R⁵ is C₁₋₆alkyl; or a pharmaceutically acceptable salt or an iii vivo hydrolysable ester thereof.
 7. A compound of formula (I) according to anyone of claims 1-6 wherein R⁶ is methyl or halo; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 8. A compound of formula (I) (as depicted in claim 1) wherein: p is 0; R² is hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or 2-ethoxyethyl or 2-pyrazol-1-ylethyl; R³ is hydrogen or bromo; R⁴ is methyl, ethyl or isopropyl; R⁵ is methyl or ethyl; R⁶ is methyl or bromo; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; with the proviso that if R⁴, R⁵ and R⁶ are all methyl then R² is not hydrogen, 2-methoxyethyl, methyl, 3-methoxypropyl or 2-ethoxyethyl.
 9. A compound of formula (I) (as depicted in claim 1) selected from: 4-(1,2-diethyl-4-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(3-methoxypropyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2,4-dimethyimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(methyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2,4-dimethylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine; 4-(1-isopropyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(36-methoxypropyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2,4-dimethylimidazol-5-yl)-2-{4-[N-(methyl)sulphamoyl]anilino}pyrimidine; 4-(1,2,4-trimethylimidazol-5-yl)-2-{4-[N-(2-pyrazol-1-ylethyl)sulphamoyl]anilino}pyrimidine; or 4-(4-bromo-2-dimethylimidazol-5-yl)-2- {4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 10. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein R¹, R², R³, R⁴, R⁶ and p are, unless otherwise specified, as defined in claim 1) comprises of: Process a) reaction of a pyrimidine of formula (II):

wherein L is a displaceable group; with an aniline of formula (III):

or Process b) reacting a compound of formula (IV):

with a compound of formula (V):

wherein T is O or S; R^(x) may be the same or different and is C₁₋₆alkyl; Process c) reacting a pyrimidine of formula (VI):

wherein X is a displaceable group; with an amine of formula (VII): R²—NH₂  (VII) or Process d) reacting a pyrimidine of formula (VIII)

with a compound of formula (IX):

where Y is a displaceable group; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
 11. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, in association with a pharmaceutically-acceptable diluent or carrier.
 12. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use in a method of treatment of the human or animal body by therapy.
 13. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use as a medicament.
 14. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, in the manufacture of a medicament for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man.
 15. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, in the manufacture of a medicament for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
 16. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, in the manufacture of a medicament for use in the treatment of cancer.
 17. The use according to claim 16 wherein the cancer is selected from leukaemia, breast cancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidney cancer, skin cancer and cancer of the vulva.
 18. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man.
 19. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
 20. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use in the treatment of cancer.
 21. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-9, for use in the treatment of leukaemia, breast cancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidney cancer, skin cancer and cancer of the vulva. 